Introduction

Iron deficiency occurs in approximately 50% of heart failure (HF) patients and is associated with reductions in functional capacity, quality of life, and life expectancy, independent of the presence of anemia or left ventricular ejection fraction (LVEF).¹ In addition to its impact on erythropoiesis and oxygen delivery, iron deficiency adversely affects oxidative metabolism and cellular immune mechanisms that impact myocardial function.¹ Myocardial iron deficiency is correlated with reduced myocardial oxygen consumption and abnormal myocardial metabolism.¹ Given these epidemiologic and pathophysiologic concerns, correction of iron deficiency has become an important target in HF management.

Treatment of iron deficiency with high dose oral iron has been studied in the IRONOUT-HF study and showed no improvement in exercise capacity at 16 weeks.² One of the potential reasons for failure of oral iron is hepcidin-mediated inhibition of iron absorption, a problem that can be avoided by using intravenous (IV) administration of iron. Multiple studies have examined the role of IV iron in patients with chronic systolic HF and iron deficiency. The FAIR-HF study randomized 459 stable outpatients with NYHA Class II-III HF and an LVEF of <45% to receive IV ferric carboxymaltose (FCM) or placebo.³ Patients treated with FCM had improvements in both quality of life and functional status. The CONFIRM-HF study of IV FCM versus placebo in 304 symptomatic outpatients with HF and iron deficiency demonstrated that treatment with FCM led to greater improvement in 6-minute walk test and quality of life.⁴ Treatment with FCM was also associated with a reduction in the risk of HF hospitalizations. The 2017 ACC/AHA focused update to the HF guidelines gives a Class IIB recommendation for use of IV iron in HF patients with iron deficiency.⁵ Accordingly, there is ongoing enthusiasm to expand our understanding of the full clinical impact (especially the effects on hospitalization burden and mortality) of IV iron in patients with both chronic and acute HF.

AFFIRM-AHF study

AFFIRM-AHF was a multicenter, randomized, double blind, placebo-controlled trial conducted to answer the question: do hospitalized, acute heart failure patients with iron deficiency benefit from iron replacement with IV ferric carboxymaltose (FCM)?⁶ The investigators included patients hospitalized with acute HF with an LVEF <50% who received at least 40 mg of IV furosemide (or equivalent) and had evidence of iron deficiency after initial clinical stabilization. Iron deficiency was defined as serum ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20% (a commonly used definition). Patients were randomized 1:1 to treatment with FCM versus placebo. Patients randomized to the treatment arm received their first dose of FCM prior to discharge and received a second dose at week 6 post-discharge. Subsequent doses were given at weeks 12 and 24 if patients remained iron deficient (as defined by above criteria) with a hemoglobin between 8-15 gm/dL. The primary endpoint was a composite of total HF hospitalizations and cardiovascular death, measured as events per 100 person-years.

A total of 1,108 patients were randomized in 1:1 fashion and were included in the final analysis. Study participants were predominantly white (95%) and were more often male (55%).  Mean LVEF was approximately 32% and mean NT-proBNP at baseline was elevated (approximately 4700 pg/dL). Mean hemoglobin was slightly above 12 gm/dL.

The conduct of the trial was affected by the onset of the COVID-19 pandemic in early 2020. Based on guidance from the European Society of Cardiology and the US Food and Drug Administration (FDA) (amongst others), the statistical analysis was modified to include a separate pre-COVID-19 sensitivity analysis in which patient events were censored starting from the date when the first COVID-19 patient was reported in each country. This analysis plan was determined prior to the final database lock.

The primary composite outcome (HF hospitalizations, cardiovascular death) occurred at a rate of 57.2 per 100 patient years in the FCM group and 72.5 per 100 patient years in the placebo group (rate ratio 0.79, p = 0.059). There was no difference in cardiovascular death (14% in both groups) but there was a significant reduction in total HF hospitalizations (rate ratio 0.74, p = 0.013). Furthermore, in the COVID-19 sensitivity analysis, the primary outcome was significantly reduced with treatment with FCM (rate ratio 0.75, p = 0.024). The investigators concluded that treatment with ferric carboxymaltose reduced the risk of heart failure hospitalizations but did not reduce the risk of cardiovascular death.

Discussion

Aptly named, the AFFIRM-AHF trial does, in fact, affirm our understanding of the benefits and limitations of IV iron replacement in patients with HF. Similar to prior experience in FAIR-HF and CONFIRM-HF, correction of iron deficiency with IV iron confers a reduction in HF hospitalizations and an improvement in patient reported symptomatology and functional status, although with no cardiovascular mortality benefit.^3,4 As such, IV iron represents an important treatment option for patients with HF, but it does not currently ascend into the upper echelon of "must use" medications that improve survival.

Perhaps most importantly, AFFIRM-AHF demonstrates that the administration of IV iron during hospitalization for acute HF decompensation is safe and effective, thus obviating the need to delay until the patient returns for follow-up in the outpatient setting. This finding continues a recent trend of HF goal-directed medical therapy (GDMT) publications that have broken down the "silos" of inpatient versus outpatient initiation of key HF medications. Despite FDA approval, both sacubitril-valsartan and the SGLT-2 inhibitors were omitted from hospital formularies (resulting in missed opportunities for initiation and low overall utilization rates) due to concern that they had not been shown to be safe to initiate in a hospitalized, acutely decompensated HF patient. This led to the design and execution of studies like PIONEER-HF⁷ and EMPA-RESPONSE AHF⁸; only after these publications were the agents made available to hospital practitioners. We welcome the findings of AFFIRM-AHF, as in our experience, the prescription and initiation of IV iron in the outpatient setting is complicated by logistical challenges.  If given in conjunction with a clinic visit, IV iron requires the establishment of vascular access and the designation of a dedicated infusion room where the patient can receive the medication and wait the appropriate amount of time to ensure no adverse reactions have occurred. Also, affordability of the infusion for patients has proven to be highly variable based on third-party reimbursement. As a result, many patients who would benefit from IV iron replacement go untreated or undertreated with the aforementioned oral medications. Furthermore, given the relative paucity of evidence-based pharmacotherapies for patients with acute HF, the AFFIRM-HF identifies treatment of iron deficiency as a meaningful intervention and supports the case for widespread screening for iron deficiency in all patients hospitalized with acute decompensated systolic heart failure.

Of note, the IV iron regimen utilized in AFFIRM-HF was initiated during hospitalization, but then completed in the outpatient setting over the course of weeks, with most patients in the FCM arm (80%) only requiring one or two infusions over the course of the study. In real world practice, providers must consider the risk of unfinished regimens due to loss of follow-up, affordability, and the logistical issues described above. A previous small publication showed that IV ferric gluconate can be given safely in a more accelerated fashion over the course of 2-3 days, a regimen we have used successfully to complete iron replacement during an inpatient encounter at our institution for years.⁹ This pragmatic strategy ensures expeditious correction of iron deficiency and can prevent the patient from shouldering the burdens of outpatient charges to complete this important therapy. However, further studies would be warranted to validate this strategy and to determine if all IV iron formulations carry the same degree of sustained clinical benefit (class effect).

In summary, AFFIRM-AHF clarifies the benefit of identifying and treating iron deficiency with IV iron in patients hospitalized with acute decompensated HF. Furthermore, we hope that this also helps to usher in an era where HF GDMT is thoughtfully prescribed at any patient encounter, whether inpatient or outpatient, as the benefits of these medications are too important to be subject to "location restrictions" that are increasingly proving to be arbitrary.

References

1. Anand IS, Pankaj G. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation 2018;138:89-98.
2. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958-66.
3. Anker SD, Colet JC, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436-48.
4. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.  Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36:657-68.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776-803.
6. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomized, controlled trial. Lancet 2020;369:1895-1904.
7. Velasquez EJ, Morrow DA, DeVore AD, et al. Angiotensin–neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539-48.
8. Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 2020;22:713-22.
9. Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy 2015;35:64-71.

Clinical Topics: Cardiovascular Care Team, COVID-19 Hub, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Statins, Acute Heart Failure, Chronic Heart Failure, Stress

Keywords: AHA Annual Scientific Sessions, AHA20, Heart Failure, Stroke Volume, Furosemide, Quality of Life, Outpatients, Sodium-Glucose Transporter 2, COVID-19, Hepcidins, Ferritins, Anemia, Iron-Deficiency, Erythropoiesis, Heart Failure, Systolic, Inpatients, Life Expectancy, Patient Discharge, Double-Blind Method, United States Food and Drug Administration, Exercise Tolerance, Follow-Up Studies, Ventricular Function, Left, Iron, Hemoglobins, Ambulatory Care, Hospitals, Prescriptions, Costs and Cost Analysis, Oxygen Consumption, Oxygen, Transferrins, Oxidative Stress

< Back to Listings